Advanced Pyrrolidine‐Carbamate Self‐Immolative Spacer with Tertiary Amine Handle Induces Superfast Cyclative Drug Release

Amine‐carbamate self‐immolative (SI) spacers represent practical and versatile tools in targeted prodrugs, but their slow degradation mechanism limits drug activation at the site of disease. We engineered a pyrrolidine‐carbamate SI spacer with a tertiary amine handle which strongly accelerates the s...

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Autores principales: Dal Corso, Alberto, Frigoli, Margaux, Prevosti, Martina, Mason, Mattia, Bucci, Raffaella, Belvisi, Laura, Pignataro, Luca, Gennari, Cesare
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2022
Materias:
Research Articles
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9544318/
https://www.ncbi.nlm.nih.gov/pubmed/35620983
http://dx.doi.org/10.1002/cmdc.202200279
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author Dal Corso, Alberto
Frigoli, Margaux
Prevosti, Martina
Mason, Mattia
Bucci, Raffaella
Belvisi, Laura
Pignataro, Luca
Gennari, Cesare
author_facet Dal Corso, Alberto
Frigoli, Margaux
Prevosti, Martina
Mason, Mattia
Bucci, Raffaella
Belvisi, Laura
Pignataro, Luca
Gennari, Cesare
author_sort Dal Corso, Alberto
collection PubMed
description Amine‐carbamate self‐immolative (SI) spacers represent practical and versatile tools in targeted prodrugs, but their slow degradation mechanism limits drug activation at the site of disease. We engineered a pyrrolidine‐carbamate SI spacer with a tertiary amine handle which strongly accelerates the spacer cyclization to give a bicyclic urea and the free hydroxy groups of either cytotoxic (Camptothecin) or immunostimulatory (Resiquimod) drugs. In silico conformational analysis and pK (a) calculations suggest a plausible mechanism for the superior efficacy of the advanced SI spacer compared to state‐of‐art analogues.
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spelling pubmed-95443182022-10-14 Advanced Pyrrolidine‐Carbamate Self‐Immolative Spacer with Tertiary Amine Handle Induces Superfast Cyclative Drug Release Dal Corso, Alberto Frigoli, Margaux Prevosti, Martina Mason, Mattia Bucci, Raffaella Belvisi, Laura Pignataro, Luca Gennari, Cesare ChemMedChem Research Articles Amine‐carbamate self‐immolative (SI) spacers represent practical and versatile tools in targeted prodrugs, but their slow degradation mechanism limits drug activation at the site of disease. We engineered a pyrrolidine‐carbamate SI spacer with a tertiary amine handle which strongly accelerates the spacer cyclization to give a bicyclic urea and the free hydroxy groups of either cytotoxic (Camptothecin) or immunostimulatory (Resiquimod) drugs. In silico conformational analysis and pK (a) calculations suggest a plausible mechanism for the superior efficacy of the advanced SI spacer compared to state‐of‐art analogues. John Wiley and Sons Inc. 2022-06-14 2022-08-03 /pmc/articles/PMC9544318/ /pubmed/35620983 http://dx.doi.org/10.1002/cmdc.202200279 Text en © 2022 The Authors. ChemMedChem published by Wiley-VCH GmbH https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
Dal Corso, Alberto
Frigoli, Margaux
Prevosti, Martina
Mason, Mattia
Bucci, Raffaella
Belvisi, Laura
Pignataro, Luca
Gennari, Cesare
Advanced Pyrrolidine‐Carbamate Self‐Immolative Spacer with Tertiary Amine Handle Induces Superfast Cyclative Drug Release
title Advanced Pyrrolidine‐Carbamate Self‐Immolative Spacer with Tertiary Amine Handle Induces Superfast Cyclative Drug Release
title_full Advanced Pyrrolidine‐Carbamate Self‐Immolative Spacer with Tertiary Amine Handle Induces Superfast Cyclative Drug Release
title_fullStr Advanced Pyrrolidine‐Carbamate Self‐Immolative Spacer with Tertiary Amine Handle Induces Superfast Cyclative Drug Release
title_full_unstemmed Advanced Pyrrolidine‐Carbamate Self‐Immolative Spacer with Tertiary Amine Handle Induces Superfast Cyclative Drug Release
title_short Advanced Pyrrolidine‐Carbamate Self‐Immolative Spacer with Tertiary Amine Handle Induces Superfast Cyclative Drug Release
title_sort advanced pyrrolidine‐carbamate self‐immolative spacer with tertiary amine handle induces superfast cyclative drug release
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9544318/
https://www.ncbi.nlm.nih.gov/pubmed/35620983
http://dx.doi.org/10.1002/cmdc.202200279
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